[(2S,3S,4S,5R)-3,4-二羟基-2-(羟基甲基)-5-(膦酰氧基甲基)四氢呋喃-2-基]磷酸二氢酯 | 79082-92-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: [(2S,3S,4S,5R)-3,4-二羟基-2-(羟基甲基)-5-(膦酰氧基甲基)四氢呋喃-2-基]磷酸二氢酯
• 英文名称: 2,6-di-O-phosphono-beta-D-fructofuranose
• 英文别名: [(2S,3S,4S,5R)-3,4-dihydroxy-2-(hydroxymethyl)-5-(phosphonooxymethyl)oxolan-2-yl] dihydrogen phosphate
• CAS: 79082-92-1
• 化学式: C₆H₁₄O₁₂P₂
• 分子量: 340.12
• InChiKey: YXWOAJXNVLXPMU-ZXXMMSQZSA-N

物化性质

• 沸点：
  760.3±70.0 °C(Predicted)
• 密度：
  2.06±0.1 g/cm3(Predicted)
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  -5
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  203
• 氢给体数：
  7
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  fructose 6-phosphate 在 potassium phosphate 、 乙二胺四乙酸 、 L-1,4-二硫代苏糖醇 、 potassium chloride 、 6-phosphofructo-2-kinasefructose-2,6-bisphosphatase 3 、 5’-三磷酸腺苷 、 magnesium chloride 作用下， 以 aq. acetate buffer 为溶剂， 生成 [(2S,3S,4S,5R)-3,4-二羟基-2-(羟基甲基)-5-(膦酰氧基甲基)四氢呋喃-2-基]磷酸二氢酯
  参考文献：
  名称：

  10.1073/pnas.2406308121

  摘要：

  Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3′-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients’ brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients’ brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases.

  DOI：

  10.1073/pnas.2406308121

文献信息

• [EN] PFKFB3 INHIBITOR AND METHODS OF USE AS AN ANTI-CANCER THERAPEUTIC<br/>[FR] INHIBITEUR DE PFKFB3 ET PROCÉDÉS D'UTILISATION EN TANT QUE PRODUIT THÉRAPEUTIQUE ANTICANCÉREUX
  申请人：ADVANCED CANCER THERAPEUTICS LLC

  公开号：WO2013148228A1

  公开（公告）日：2013-10-03

  A novel compound, (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one, is provided herein. (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one is an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) with surprisingly superior efficacy and pharmacodynamic properties in vitro and in vivo. Also provided are pharmaceutical compositions including the compound and methods of use of the compound in treating cancer and tumors in vivo, as well as inhibiting glycolytic flux and PFKFB3 enzymatic activity in cells.

  本文提供了一种新的化合物，即(E)-1-(吡啶-4-基)-3-(7-(三氟甲基)喹啉-2-基)-丙-2-烯-1-酮。 (E)-1-(吡啶-4-基)-3-(7-(三氟甲基)喹啉-2-基)-丙-2-烯-1-酮是6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶3 (PFKFB3)的抑制剂，在体外和体内具有惊人的优越疗效和药效学特性。还提供了包括该化合物的制药组合物以及在体内治疗癌症和肿瘤，以及抑制细胞中糖酵解通量和PFKFB3酶活性的方法。
• INHIBITORS OF FRUCTOSE 1,6-BISPHOSPHATASE AND METHODS OF USE THEREOF
  申请人：Kantrowitz Evan R.

  公开号：US20120028892A1

  公开（公告）日：2012-02-02

  The invention is directed to a compound according to formula (I). The compounds of formula (I) include prodrugs, pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof. The invention is also directed to a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier and to methods for treating diabetes by administering such a pharmaceutical composition alone or in combination with other therapeutic agents. The invention is also directed to inhibitors of fructose-1,6-bisphosphatase.

  该发明涉及一种符合式（I）的化合物。符合式（I）的化合物包括前药、药物可接受的盐、立体异构体混合物及其对映体。该发明还涉及一种药物组合物，包括符合式（I）的化合物和药物可接受的载体，以及通过单独或与其他治疗剂联合给药该药物组合物治疗糖尿病的方法。该发明还涉及果糖-1,6-二磷酸酶的抑制剂。
• PFKFB3 INHIBITOR AND METHODS OF USE AS AN ANTI-CANCER THERAPEUTIC
  申请人：ADVANCED CANCER THERAPEUTICS, LLC

  公开号：US20150064175A1

  公开（公告）日：2015-03-05

  A novel compound, (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one, is provided herein. (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one is an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) with surprisingly superior efficacy and pharmacodynamic properties in vitro and in vivo. Also provided are pharmaceutical compositions including the compound and methods of use of the compound in treating cancer and tumors in vivo, as well as inhibiting glycolytic flux and PFKFB3 enzymatic activity in cells.

  本文提供了一种新化合物，即(E)-1-(吡啶-4-基)-3-(7-(三氟甲基)喹啉-2-基)-丙-2-烯-1-酮。 (E)-1-(吡啶-4-基)-3-(7-(三氟甲基)喹啉-2-基)-丙-2-烯-1-酮是6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3 (PFKFB3)的抑制剂，在体外和体内具有惊人的优越疗效和药理学特性。还提供了包括该化合物的制药组合物以及使用该化合物在体内治疗癌症和肿瘤以及抑制细胞中的糖酵解通量和PFKFB3酶活性的方法。
• Liposome comprising a novel phosphate as membrane constituent, liposome preparations and cosmetic preparations comprising said phosphate
  申请人：KAO CORPORATION

  公开号：EP0370491A2

  公开（公告）日：1990-05-30

  A novel monophosphate and a novel diphosphate prepared by a phosphatidyl transfer reaction of a phospholipid and an alcohol in the presence of phospholipase D are disclosed. The phosphates can independently or together form small and stable liposomes which can include active components therein. Cosmetic compositions comprising these phosphates or liposomes penetrate well into the hair and the skin, and exhibit long-lasting excellent moisture-retaining, beauty, skin-activation effects.

  本研究公开了一种新型单磷酸盐和一种新型二磷酸盐，它们是在磷脂酶 D 的存在下，通过磷脂和醇的磷脂酰转移反应制备的。这些磷酸盐可单独或共同形成小而稳定的脂质体，其中可包含活性成分。包含这些磷酸盐或脂质体的化妆品组合物可以很好地渗透到头发和皮肤中，并表现出持久的出色保湿、美容和活肤效果。
• Antidiabetic alpha-substituted phosphonates
  申请人：AMERICAN CYANAMID COMPANY

  公开号：EP0354322A2

  公开（公告）日：1990-02-14

  Alpha-substituted phosphonates are disclosed which stimulate the enzyme fructose-1,6-bisphosphatase and inhibit the enzyme 6-phosphofructo-1-kinase, there­by lowering glucose levels in mammals. These alpha-­substituted phosphonates may thus be used to treat hyperglycemia and/or diabetes. Processes for the syn­thesis of the alpha-substituted phosphonates are also disclosed.

  已公开的α-取代膦酸盐可刺激果糖-1,6-二磷酸酶，抑制6-磷酸果糖-1-激酶，从而降低哺乳动物体内的葡萄糖水平。因此，这些α-取代膦酸盐可用于治疗高血糖和/或糖尿病。还公开了合成α-取代膦酸盐的工艺。